Electrical neuromodulation is an important strategy for treating chronic pain conditions that are refractory to pharmacotherapies. However, currently available neurostimulation pain therapies are associated with limited efficacy and side effects. We created novel Safe Direct Current Stimulation (SDCS) that enables implantable neuroelectronic prostheses to safely modulate neuronal activity by using ionic direct current (iDC). Our preliminary studies provide promising evidence that iDC applied at peripheral nerves induces effective and reversible inhibition of neural activity in pain pathways. Intriguingly, iDC may be optimized to preferentially inhibit ?pain? signals, while allowing the other nerve signals to pass. The central goal of our study is to uncover neurophysiologic mechanisms, optimize stimulation parameters, and establish the experimental framework for advancing the development of novel SDCS-based neuroelectronic prostheses for precision pain treatment. In Aim 1, we will examine how iDC modulates the conduction and excitability of different subtypes of afferent sensory neurons in a rat model of neuropathic pain. By recording compound action potentials and activity in teased nerve fibers, we will determine how to optimize the polarity, intensity, and duration of iDC in a way that preferentially suppresses propagation of ?pain? signals in the peripheral nervous system. In Aim 2, we will uncover spinal neurophysiologic mechanisms for pain inhibition by iDC. Specifically, we will record local field potential in dorsal horn to examine if iDC differentially affects spinal transmission of sensory inputs from nociceptive C-fibers and non-nociceptive A?-fibers. Single-unit recording will be used to further determine how iDC affects responses of individual pain-processing dorsal horn neurons to peripheral stimuli. If iDC induces neuronal excitation, we will determine if the excitation can be reduced by using multipolar and phasic-array iDC paradigms. In Aim 3, we will conduct animal behavior tests to optimize the suppression of pain manifestations by iDC and examine potential side effects. Histologic and immunocytochemical studies will be used to evaluate the biosafety of iDC with short- and long-term use. Novel non-pharmacologic strategies are greatly needed for chronic pain treatment, and the performance of SDCS in biological systems is just now being explored. Our findings will help to conceptualize the biological basis of SDCS techniques for precision pain inhibition. Based on iDC mechanisms, our findings will provide rationales and critical insights for the development of testable SDCS-based ?electroceuticals? that may revolutionize current approaches to chronic pain treatment.